19-nor-6,6-ethylene-20-spiroxenes

ABSTRACT

Novel 19-nor-6,6-ethylene-3-oxo-20-spirox-4-enes (or 4,14dienes) are provided, prepared from the corresponding 19-nor-3oxo-spirox-4-enes (or 4,14-dienes). The compounds are useful as orally-effective antiestrogens, and are also anabolic agents having low androgenicity.

United States Patent Arth et al. June 27, 1972 54]l9-NOR-6,6-ETHYLENE-20- [56] References Cited SPIROXENES UNITED STATESPATENTS [72] Inventors: Glen E. Arth, Cranford; Gary H. Rasmus-3,422,097 1/1969 Kerwin ..260/239.57

son, Watchung, both of NJ. 3,497,498 2/1970 Georgian .260/23955 [73]Assignee: Merck & Co., Inc., Rahway, NJ. Primary Examiner Hemy A. French[22] Filed: June 18, 1970 v Attorney-l. Louis Wolk, 1. Jerome Behan andl-lesna J. 21 Appl. No.: 47,606

r [57] ABSTRACT [52] "260/239'55 5 Novell9-nor-6,6-ethylene-3-oxo-2Q-spirox-4-enes "(or 4,14- Int Cl a g /00dienes) are provided, prepared from the corresponding 19- [58] Field ofSearch ../Machine Searched Steroids nor 3 oXo sp"ox-4 enes (or4J4dlenes) The compounds are useful as orally-effective antiestrogens,and are also anabolic agents having low androgenicity.

10 Claims, No Drawings BACKGROUND OF THE INVENTION Novel. l9nor-6,6-ethylene-3-oxo-20-spirox-4-enes (or 4,14-dienes) are provided,prepared from the corresponding 19-nor-3-oxo-spirox-4-enes (or4,14-dienes). The compounds are useful as orally-effectiveantiestrogens, and are also anabolic agents having low androgenicity.

DESCRIPTION OF THE PRIOR ART U. 5. Patent 3,422,097 describesl9-nor-6,6-ethylenespirolactones, disclosed as having androgenic andanabolic activity. It is desirable, however, to provide compounds inwhich the anabolic activity is high and the androgenic activity is lowto prevent undesirable side-effects accompanying the use of anandrogenic product.

SUMMARY OF THE INVENTION The compounds of the present invention arel9'-nor-3-oxo- 6,6-ethylene--spirox-4-enes which possess a highanabolic/androgenic ratio. This high anabolic/androgenic ratio issurprising, in light of the prior art teachings of other compounds g inthe series. In addition, the compounds possess a potent anti- Flow SheetI R1\0 RI H H O= CHaO- \J A v i in O 0 R1 R1 H H I .z (EH 0 N CH2 CH0 Inthe above scheme, Compounds I and II are the desired end-products. R iseither H or CH,; the broken line is an optional double bond. In CompoundII, R represents hydrogen,

loweralkyl having one to six carbon atoms, loweralkanoyl having one tosix carbon atoms, or tetrahydropyranyl or tetrahydrofuranyl.

The process used to prepare the compounds of this invention employs asits starting material the Compound A, l9-nor- 20-spirox-4-en-3-oneorl9-nor-20-spirox-4,l4-dien-3-one. The starting compound is firstconverted to a 3-enol ether (Compound B) by treatment with atriloweralkyl orthoformate such as trimethyl or triethyl orthoformate inthe corresponding alcohol solvent in the presence of an'acid catalystsuch as 2,4-dinitrobenzene sulfonic acid.' The resulting 3- 'methoxy (orethoxy) 3,5-diene (or 3,5,l4-triene) is formylated at the 6-position bytreatment with the Vilsmeier reagent. This reagent, which consists ofphosgene or phosphonyl chloride and dimethylformamide, reacts in ananhydrous medium with the diene atposition-Gto give an iminiumintermediate which is then hydrolyzed in acid tothe 6-formyl compound(C). The formyl group is then reduced either by catalytic means or bylithium aluminum hydride or sodium borohydride to give a 6-hydroxymethylcompound and then dehydrated with a reagent such as glacial acetic acid,ptoluene sulfonic acid, or sulfuric acid to give the 6-methylenecompound (D). Compound I is formed by means of a reagent which iscapable of adding a methylene group across the 6- methylene double bond.A suitable reagent is dimethyl sulfoxonium methylide, which is formed insitu by reaction of dimethyl sulfoxide methiodide with a strong basesuch as sodium hydride. An alternate process utilizes diazomethane toadd a pyrozolinyl group at 6, followed by pyrolysis to produce the6,6-ethylene substituent.

Further product compounds of the invention, Compound II, can be preparedby alkylating or alkanoylating a 3-hydroxyl group. The 3-keto group isfirst reduced using, for example, sodium borohydride in methanol at 0 upto theboiling point of methanol. The 3-ol group can be used withoutfurther reaction or can be converted to an ether or ester by one ofseveral procedures.

' For instance, Compound II can be treated with a strong base such asalkali metal alkyls or alkali metal hydrides, e.g., methyl lithium,sodium hydride and the like, forming the alkoxide. Thisisfollowed byaddition of aloweralkyl sulfate-or loweralkyl halide leading toloweralkyl ethers of II (R=H). If

an ester is preferred, a suitable reagent such as a loweralkanoylanhydride or a loweralkanoyl chloride, is allowed to react with II (R=H)in a basic medium such as pyridine or a trialkylamine in an inertsolvent such as ether or benzene.

Where the R group in Compound I! is a heterocycloalkoxy group such asthe tetrahydropyranyl or the tetrahydrofuranyl groups, a different modeof synthesis is used. The allylic alcohol is treated with the desiredheterocycloalkene such as dihydropyran or dihydrofuran in the presenceof an acyl halide or anhydrous mineral acid. The more preferred acylhalides include an aryl sulfonyl halide such as benzene sulfonylchloride or p-toluene sulfonyl chloride.

When the chosen starting material in Flow Sheet I is the 4,14-dien-3-onecompound, it can be prepared using the following novel reactionsynthesis shown in Flow Sheet II. The starting compound in thissynthesis is the ethylene ketal of estrone loweralkyl, preferablymethyl, ether (Compound F), which is brominated at position-l6 usingpyridinium bromide perbromide. In general, the bromination reactiontakes place in an inert organic solvent at low temperatures (0-25 C.).

The estrone ether and the perbromide are employed in ap- 1dehydrobromination reaction is effected by refluxing in a high boilingsolvent (i.e., about l20-200 C.) in the presence of an alkali metalalkoxide, e.g., potassium-t-butoxide. The mixture is refluxed forseveral hours, cooled, and the product extracted with an aromatichydrocarbon. After evaporation and E O recrystallization, the product His recovered.

In the third step, the l7,l7-ethylene dioxy group of H is 5 transformedto the l7-keto derivative (J), by means of dilute acid, such asp-toluene sulfonic acid, in an aqueous-organic solvent mixture. Theorganic solvent is preferably acetone. The product J is recovered afterconcentration and filtration. I

Compound J is then converted to the l7-acetoxy-l,3,5( 10 10 CH3)),l4,l6-pentaene derivative (K) by treatment with p-toluene sulfonicacid and acetic anhydride. The pentaene K is then J H reduced to thetetraene-l7-ol Compound L. The reduction conditions utilize sodiumborohydride in aqueous alcohol, l preferably methanol or ethanol. Excesshydride is neutralized by the addition of acid such as glacial aceticacid. The product R1 OAc (L) is recovered by the concentration oforganic solvent ex- I I tracts. Q

The alcohol group at 17 of Compound L is then selectively I oxidized tothe l7-keto derivative (M). A suitable oxidation 20 m system is adipyridine-chromium VI complex in a solvent such as methylene chloride.The oxidation proceeds rapidly at on O C O 1 room temperature, 7 a

CompoundM is then treated with allyl magnesium chloride K L in ether toyield the l7B-hydroxy-l7a-allyl Compound (N).

The reaction proceeds within 1-2 hours or less at room teml perature.The l7a-allyl substituent is transformed to the 17a-(3-hydroxypropyl)-l7B-hydr0xyCompound (0). An excess R1 HO of diboranein an organic solvent (suitably tetrahydrofuran) in ----CHCH=CH2 thepresence of 2-methyl-2-butene is first employed at low temperatures (-20to 0 C.). The reaction mixture is then made basic, suitably with NaOH;then hydrogen peroxide is added andthe mixture allowed to stand 8-12hours at room temperature. The product Compound (0) is a keyintermediate. By reference to the Flow Sheet, it can be seen that itCH3) can be treated following at least two separate processes to yieldthe desired A spiroxenone (Compound A). v N

The first process of reaction Compound 0 is a three-step R HOCH CHQOHprocedure via Compounds (P) and (Q). The first step, yield- 4 1 2 ingCompound P, is a Birch reduction using metallic lithium I and t-butanolin a solvent mixture of liquid ammonia and diethyl ether. Afterrefluxing for 3-4 hours, the product (P) is separated and suspended inalcohol. The suspension is v I acidified with HCI and stirred at roomtemperature. After CH3O about 20-24 hours, the mixture is neutralizedand the product Compound Q recovered. The final step is the ring closureof 0 the spiroxa ring using p-toluene sulfonyl chloride inpyridine. V

Alternatively, Compound Q can first be converted to the spiroxene byclosing the l7B-hydroxy-l7a-(3-hydroxypropyl) substituents usingp-toluene sulfonyl chloride in l pyridine, followed by the Birchreduction and acid-catalyzed OH hydrolysis to yield the final desired Aspiroxenone, Com- R \CHzCHOCHZOH pound A. 5 5 Although the abovereaction sequence is illustrated using I the 3-methoxy ether of thestarting compound, other loweralkoxy compounds could be used with equalsuccess. Loweralkoxy is used to mean all alkoxy groups having one to sixcarbon atoms. i 011 0 3 1 0 The 6,6-ethylene-spiroxene compounds ofthe-invention, having a high anabolic/androgenic ratio are useful whenit is desired to increase body weight and build muscle tissue withoutstimulating an androgenic response. In addition, the compoundl9-nor-20-spirox-4-en-3one possess a high degree of oral estrogenantagonist activity.

The following examples are used to illustrate the invention. Variousobvious modifications will occur to those skilled in the art, and thosemodifications are to be considered part of the invention.

EXAMPLE 1 3-Methoxyl 9-nor-20-spiroxa-3 ,S-diene A solution of 2.4 g. ofl9-nor-20-spirox-4-en-3-one in 55 ml. of methanol is prepared by heatingthe solvent slightly during addition of the steroid. The solution isthen cooled to C. 275 Mg. of 2,4-dinitrobenzene sulfonic acid and 5.5cc. of trimethyl orthoformate is then added and stirred for 10 minutes.Pyridine is then added 16 drops) and 55 ml. of water is also addeddropwise. Precipitation of the product occurs readily. The precipitateis filtered and dried. Following recrystallization from methanolcontaining a small amount of pyridine, the product,3-methoxy-l9-nor-20-spiroxa-3,5- diene, is obtained, m.p. 9497 C.

EXAMPLE 2 3-Methoxy- 6-forrnyll 9-nor-20-spiroxa-3 ,S-diene The steroid(200 mg.) prepared in Example 1 in 2 ml. of methylene chloridecontaining a small amount of pyridine (.1 ml. of pyridine to 40 ml. ofmethylene chloride) is stirred at 0 A solution of Vilsmeier reagent hadbeen previously prepared at 0 from 2.8 cc. of phosphoryl chloride(redistilled) and 8.3 ml. of dimethylformarnide in 25 ml. of methylenechloride. 1.2 MI. of this Vilsmeier reagent is added to the steroidsolution. The resulting solution is stirred at 0 C. for 2 hours.

20 percent Aqueous sodium acetate (2 ml.) is added and stirringcontinued for 15 minutes at room temperature. Diethyl ether is added andthe organic layerseparated. After washing with a 10% Nal-lCO solutionand water, the organic fraction is dried and concentrated down to aresidue of the product.

After recrystallization from diethyl ether, the product, 3-methoxy-fi-formyl-l9-nor-20-spiroxa-3,5-diene, m.p. 1l4-12 0 C., isrecovered.

. I EXAMPLE 3 6-Methylenel 9-nor-20-spir0x-4-en-3-one 125 Mg. of lithiumaluminum hydride is stirred in cc. of ether at 0 C. The3-methoxy-6-formyll 9-nor-20-spiroxa-3,5- diene (1.0 g.) dissolved in 15cc. of dry tetrahydrofuran is added. After stirring at 0 C. for 10minutes, the mixture is added to 100 ml. of a 2.5 N hydrochloric acidsolution. The stirring is continued at room temperature for one-halfhour.

A precipitate is formed gradually and is filtered and recovered. Therest of the product is extracted from the aqueous solution with ether.The ether extracts are combined and washed with sodium bicarbonatesolution, then water, and dried and the solvent evaporated. The crudeproduct fractions are combined and used without further purification inthe next example.

X MPLE 4 6,6-Ethylene-l9-nor-20-spirox-4-en-3-one ln a dry Z-neckround-bottom flask is placed [.28 grams of dimethyl sulfoxide methiodidedissolved in 22.5 ml. of dry dimethyl sulfoxide. 275 Mg. of sodiumhydride is added and the solution stirred vigorously under nitrogen forone-half hour until the solution is clear.

The 6-methylene steroid prepared in Example 3, approximately 1 g., isadded to the reagent after dissolving in ml. of tetrahydrofuran. Themixture is stirred for minutes.

The reaction is quenched by the addition of water and the product isextracted with ether. The exter extract is washed with water, dried, andconcentrated. A crude product is obtained which is purified bychromatography over silica gel. it is diethylether to a solution of 18g. of KOH in 30 ml. of

water. This solution is placed in a 500 ml. of 3-necked reaction flaskfitted with dropping funnel, efficient condenser and water bath. Thereceiving flask is connected with second flask containing 30 ml. ofdiethylether. Both are cooled to 0 C. The inlet tube of the secondreceiver is dipped below the surface of the ether. The water bath isthen heated to 70 C. As distillation of the ether started, a solution of64.5 g. of p-tolylsulfonylmethylnitrosarnide in about 600 ml. ofdiethylether is added through the dropping funnel over a period of 3hours. When the dropping funnel is empty, another 50 ml. of ether areadded slowly and distillation continued until the distillate iscolorless. The combined ethereal distillate contains about 9 g. ofdiazomethanol which is dried over KOH, and used as a solution in thenext step.

b. 3-Oxol 9-nor-spiro( 20-spirox-4-en-6,3 l -pyrazoline) To thediazomethane solution prepared above is added 4.5 g. of the 6-methylenecompound of Example 3. The solution is stirred at room temperature for18 hours. The excess diazomethane is then distilled off to a flaskcontaining acetic acid. The solid product is dried under vacuum, and theyield is calculated to be almost quantitative. A small portion isrecrystallized from diethylether, m.p. 220-225 C. The remainder of theproduct, 3-oxol 9-norspiro(20-spirox-4en-6,3 1 pyrazoline), is usedwithout purification in the next step.

c. 6,6-Ethylene-l9-nor-20-spirox-4-en-3-one The above pyrazolinecompound is heated in a sublimator at high vacuum at 230-250 C. for 1hour. The product is collected on the cold finger of the sublimator.

The crude product is purified by column chromatography. It is passedthrough a column packed with silica gel, and eluted first with benzene,then with increase percentage of diethylether in benzene, up to 10percent ether in benzene.

2.4 G. of product is obtained. After recrystallization from heptane, themelting point of the product, 6,6-ethylene-l9- nor-20-spirox-4-en-3-one,is 868 7 C.

EXAMPLE 6 6,6-Ethylene-l9-nor-20-spirox-4-en-3-ol 10 G. of6,6-ethylene-l9-nor-20-spirox-4-en-3-one as prepared in Example 4 orExample 5 is dissolved in 350 ml. of methanol. To this solution is added3.8 g. of sodium borohydride in 15 ml. of cold water. The addition iscarried out during 5 minutes at 0 C. with stirring and the reactionmixture is then allowed to come to room temperature over a period of 2hours. The reaction mixture is quenched by allowing to cool to roomtemperature and is poured into water and filtered. The filtered reactionis washed with water, dried, and recrystallized from ether to give6,6-ethylene-l9-nor-20- spirox-4-en-3-ol.

EXAMPLE 7 3-Ethoxy-6,6-ethylene- 19-nor-20-spirox-4-ene A solution of5.3 g. of the 3-0] steroid prepared in Example 6 is prepared in 250 ml.of dry dimethoxy ethane, cooled to 0 C., and treated with a solution of1.6 N methyl lithium in ether until no further evolution of a gas isnoted. The resulting solution is stirred at about 0 C. for about 10minutes and then treated with 25 ml. of ethyl bromide. The temperatureof the solution is permitted to rise to ambient temperature and stirredfor about 16 hours. The reaction is quenched by the addition of 25 g. ofsolid sodium bicarbonate followed by 250 ml. of water. The resultingsuspension is stirred for a further 10 hours and concentrated underreduced pressure to remove the bulk of the organic solvent. The Theresidual aqueous mixture is extracted with ether. The ether layer iswashed and dried and concentrated to yield a solid product.Recrystallization from methanol yields 3-ethoxy-6,6-ethylene-19-nor-20-spirox4-ene, the desired product.

In accordance with the above procedure but where in place of ethylbromide there is utilized dimethyl sulfate or butyl bromide, theproducts 3-methoxy-6,6-ethylene-l9-nor-20-spirox- 4-ene, or3-butoxy-6,6ethylene-l9-nor-20-spirox-4-ene are obtained.

EXAMPLE 8 3-Tetrahydropyranyloxy-6 ,6-ethylene- 19-nor-20-spirox-4-ene Asolution of l 15 mg. of the 3-hydroxy steroid prepared in Example 6 in 1ml. of redistilled dihydropyran, and 25 mg. of p-toluene sulfonylchloride is prepared. The mixture is stirred at ambient temperature for22 hours. 0.25 Ml. of pyridine are added and the mixture concentratedunder reduced pressure to remove excess dihydropyran. The residue isstirred for one hour with 1.5 ml. of 5 percent aqueous sodiumbicarbonate and the mixture extracted with chloroform. The chloroformlayer is separated, washed with water, and dried under sodium sulfateand concentrated to yield a residue. Trituration of the residue withpentane yields 3-tetrahydropyranyloxy-6,6- ethylenel9-nor-20-spirox-4-ene.

In accordance with following the procedure above but where in place ofdihydropyran there is utilized dihydrofuran, there is obtained3-tetrahydrofuranyloxy-6,6-ethylenel 9-nor- 20-spirox-4-ene.

EXAMPLE 9 l6-Bromo-l7,l7-ethylenedioxy-3-methoxyestra-1,3 ,5( 10)-triene To a solution of 34 g. (0.104 mole) of the ethylene ketal ofestrone methyl ether in 1,100 ml. of tetrahydrofuran is added withstirring at 35.5 g., (0.1 l mole) of pyridinium bromide perbromide inportions over minutes. The mixture is stirred at 0 for one hour, theorange bromine color being replaced by yellow. The insoluble material isremoved by filtration and the filtrate is concentrated to about 100 ml.It is then added to an excess of 5% sodium bicarbonate solution withstirring. The separated product is isolated by filtration and washedwell with water. After drying under reduced pressure the solid isrecrystallized from ethyl acetate to give 29.1 g. of prisms, m.p.

product is identified as l6-bro mo-l7, l 7-ethylenedioxy-3-methoxyestra-l,3,5( l0) triene.

EXAMPLE 10 17,17-Ethylenedioxy-3-methoxyestra-l,3,5( 10), l S-tetraene Asuspension of l 13 g. of freshly prepared potassium t-butoxide in 1,500ml. of xylene is heated until 250 ml. of the solvent is removed. Thebromoketal prepared in Example 9 (32.3 g., 0.079 mole) is added andthemixture refluxed under nitrogen for 18 hours. After cooling to roomtemperature 500 g. of ice is added to the reaction mixture. The phasesare separated and the aqueous phase extracted with benzene. The combinedorganic phases are washed well with water, then with saturated sodiumchloride solution and dried. Concentration gives a pink crystallineresidue which on separation from ethanol yields 22.8 g. of plates, m.p.122l23.5, identified as I l7,17-ethylenedioxy-eh-methoxyestra-l ,3 ,5(l0), 1 S-tetraene.

EXAMPLE l1 3-Methoxyestra-1,3 ,5( l0),l5tetraene-17-one A solution of 10g. (0.031 mole) of the ketal prepared in Ex: ample 10 and 500 mg. ofp-toluene sulfonic acid hydrate in a mixture of 750 ml. of acetone and125 ml. of water is stirred at room temperature for 105 minutes. It isthen treated with 800 mg. of sodium bicarbonate. After concentration ofthe mixture under reduced pressure to about one-half of its originalvolume it is diluted with one liter of saturated sodium chloridesolution. The separated product is isolated by filtration,

washed well with water and then dried. Recrystallization from 900 ml. ofheptane gives 6.7 g. of heavy prisms, m.p. l76-l 79 Furtherrecrystallization yielded 5.02 g. of 3-methoxyestra- 1,3,5( 10), lS-tetraene-l 7-one, m.p. l80-l 82.

EXAMPLE 12 17-Acetoxy-3-methoxyestral ,3,5( 10),l4,16-pentaene To asolution of 690 mg. (2.44 mmoles) of the enone prepared in Example 1 lin 20 ml. of acetic anhydride is added mg. of p-toluene sulfonic acid.The mixture is stirred at room temperature overnight and thenconcentrated under reduced pressure (100 mm) at 90 to about one-third ofits original volume. The remaining anhydride is removed by treatmentwith a saturated solution of sodium bicarbonate. The product isextracted into diethyl ether and worked up to give a crystalline,colored residue. Recrystallization from methanol gives 465 mg. of theproduct, l7-acetoxy-3-methoxyestra-l ,3,5( l0),14, l 6-pentaene.

EXAMPLE l3 3-Methoxyestral ,3 ,5 10), l4-tetraene- 1 73-01 To a solutionof 1.367 g. (4.2 mmoles) of the enol acetate prepared in Example 12 in75 ml. of ethanol is added at 0 a solution of 825 mg. of sodiumborohydride in 75 ml. of ethanol-water (10:3). The mixture is kept at5-l0 for 16 hours and then at room temperature for 4 hours. ,Glacialacetic acid is added to neutralize the excess hydride and the resultingmixture concentrated to near dryness under reduced pressure. The residueis extracted with ethylacetate and the resulting extract is washed,dried and concentrated tov give a glass which crystallized ontrituration with alcohol. Recrystallization from isopropanol yields 982mg. of fine needles, m.p.

ll2l 14. The product is identified as 3-methoxyestra- 1,3,5( 10),l4-tetraen-17B-ol.

EXAMPLE l4 3Methoxyestral ,3 ,5 10), l 4-tetraenl 7-one A solution of9.3 g. (0.0328 mole). of 3-methoxyestra- 1,3,5( 10), l4-tetraen-17B-olprepared as in Example 13in 300 ml. of methylene chloride is added at arapid dropwise rate to a stirred suspension of 46.5 g. (0.18 mole) ofdipyridinechromium (VI) complex in 800 ml. of methylene chloride at roomtemperature. The mixture is stirred 45 minutes and then filtered. Theresidue is washed with ethyl acetate and the organic layers arecombined. Water is added to the filtrates and sufficient ethyl acetateis added to make the organic layer less dense than water. After theorganic layer is washed with water, it is dried over sodium sulfate andconcentrated to leave -10 g. of crystalline residue. Recrystallizationfrom methanol gives 7 g. of the desired 3methoxyestra-l,3,5( l0l4-tetraen-l7-one, m.p. 98-l00.

EXAMPLE 15 3-Methoxyestral ,3,5( 10), l 4-tetraenl 7a-allyl- 1 73-01 5.3G. of the steroid prepared in Example 14 is dissolved in 268 ml. ofdiethyl ether and cooled to 0 C. Ml. of 3M allylmagnesium chloride intetrahydrofuran is added and the mixture stirred at room temperature for1 hour. The solution is quenched with ammonium chloride and extractedwith ethyl acetate, then washed with water. After drying andevaporating, a yellow oil is obtained which weighs 8.6 g.Recrystallization from methanol yields a white crystalline solid. 4.0 G.of the product, 3-methoxyestra-l,3,5(10),]4-tetraen-l7a-allyll 7B-ol, isrecovered.

EXAMPLE l6 3-Methoxyestral ,3,5( 10), l 4-tetraen- 1 7a-( 3hydroxypropyl 1 73-01 A dry flask under N atmosphere is prepared forreaction by adding 14 ml. of 1M diborane (20 percent excess) in 14 ml.distilled tetrahydrofuran. The vessel and contents are cooled to 20 C.and 5 ml. of 2-methyl-2-butene in 5 ml. of tetrahydrofuran is added andstirred for one-half hour. The temperature is maintained at -20 C. Tothe flask is added 4.0 g. of the allylic alcohol steroid prepared inExample 15 in 20 ml. of tetrahydrofuran. The flask is stirred at 0 C.for 2 hours. After cooling to 20 C., 14 ml. of 3N NaOH is added slowly.The reaction mixture foams and when foaming ceases, 14 ml.

evaporated. A white crystalline powder melting at 156-158 C. isrecrystallized from methanol, which is identified as 3-methoxyestra-2,5( 10),14-trien-17a-(3-hydroxy-propyl)-17B- EXAMPLE 18Estra-4, l 4-dien- 1 7a 3 -hydroxypropyl l 7,B-ol-3-one 100 Mg. of thepowder prepared in Example 17 is suspended in 3.3 ml. of ethanol in aseparate reaction flask. 0.4 M1. of a 2.5 N hydrochloric acid solutionis then added and the reaction stirred at room temperature. After 24hours, it is neutralized with aqueous sodium bicarbonate. The ethanol isremoved by evaporation and the residue is crystallized, filtered, anddried, and the product was identified as estra-4,14- dien- 1 7a-( 3-hydroxypropyl-17/3-o1-3-one, m.p. l 85187 C. EXAMPLE 19l9-Nor-20-spiroxa-4, 1 4-dien-3-one 820 Mg. of the diol prepared inExample 18 is dissolved in 8' cc. of pyridine and cooled to 0 C. To thissolution is added 820 mg. of p-toluenesulfonyl chloride and the mixturestirred at room temperature overnight. The solution is diluted slowlywith water and an oily substance is separated. This oil, afterextraction with ethyl acetate and washing with water, is dried andevaporated yielding 731 mg. of a dark oil. The oil is purified by thinlayer chromatography on a silica gel with a 2 percentmethanol/chloroform eluant.The product is taken up in benzene andrecrystallized from a 10 percent ethanol/benzene mixture. Massspectograph analysis indicates that the product,19-nor-20-spiroxa-4,14-dien-3-one, is prepared, melting at 7274 C.

EXAMPLE 3-Methoxy-19-nor-20-spiroxa-1,3,5( 10 14-tetraene 800 Mg. of thediol prepared in Example 16 is dissolved in 8 cc. of pyridine and cooledto 0 C. To this solution is added 800 mg. of p-toluenesulfonyl chlorideand the mixture stirred at room temperature overnight. The solution isthen diluted with water. The crude product is recovered as an oil, whichafter purification and recrystallization, is identified as 3- methoxy l9-nor-20-spiroxa- 1 ,3,5( 10), l 4-tetraene.

EXAMPLE 21 19-Nor-20-spiroxa-4, l 4-dien-3-one The product prepared inExample 20 is treated withanhydrous ammonia and solid lithium int-butanol following the procedure of Example 17. The product obtained isl9-nor-20- spiroxa-3-methoxy-2,5(10),14-triene. This latter product isthen treated with acid following the procedure of Example 18 to yieldthe 19-nor-20-spiroxa-4,14-dien-3-one final product, m.p. 7274 C.

What is claimed is:

1. A compound having the formula of 30 percent aqueous H 0 is added. Themixture is allowed to stand overnight at room temperature. The reactionis quenched by dilution with water and the tetrahydrofuran is evaporatedunder vacuum. The residue is crystallized, filtered,

To a dry flask equipped with a Dry Ice condenser and magnetic stirrerdevice under a N atmosphere is added 0.5 g. of the steroid (prepared inExample 16) suspended in 7 ml. of tbutanol and 7 ml. of diethyl ether.20 Ml. of anhydrous liquid ammonia is added to the flask. Sufficientsolid lithium wire is then added to turn the solution dark blue. Themixture is refluxed for 3-4 hours. Methanol is added to quench thereaction and the arm'nonia allowed to evaporate overnight under the Nstream. At this point, ml. of water and 25 ml. of

' wherein the broken line indicates an optional double bond,

and purified. 2.4 G. of 3-methoxyestra-l,3,5(10),l4-tetraenand R iseither H or CH 2. The compound of claim 1 which is l9-nor-20-spirox-6,6-ethylene-4-en-3-one.

3. The compound which is 19-nor-20-spirox-6,6-ethylene--4,14-dien-3-one.

4. A compound having the formula wherein R is hydrogen, loweralkylhaving one to six carbon atoms, loweralkanoyl having one to six carbonatoms, tetrahydropyranyl, or tetrahydrofuranyl, R is either H or CH andthe broken line indicates an optional double bond.

5. The compound of claim 4 which is 6,6-ethylene-l9-nor-20-spirox-4-en-3-OR, where R is hydrogen, loweralkyl having one to sixcarbon atoms, loweralkanoyl having one to six carbon atoms,tetrahydropyranyl, or tetrahydrofuranyl.

6. The compound which is 6,6-ethylene-19-nor-20-spirox- 4,14-dien-3-OR,where R is hydrogen, lower alkyl having one to six carbon atoms,loweralkanoyl having one to six carbon atoms, tetrahydropyranyl, ortetrahydrofuranyl.

7. The compound of claim 4 wherein R is hydrogen.

8. The compound of claim 4 wherein R is methyl.

9. The compound of claim 4 wherein R is acetyl.

10. The compound of claim 4 wherein R is tetrahydropyranyl.

Patent N0. 3 ,673,180 Dated June 27, 1972 h1v( ntor(s) A-Tth t 31. 3

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Signed and sealed this 13th day of February 1973.

(SEAL) Attest:

EDWARD M.FLETCIIER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents FORM PC4050 (10'69) USCOMM-DC 60376-P69 fi U.S. GOVERNMENTPRINTING DFFICE 95 0365'334.

2. The compound of claim 1 which is19-nor-20-spirox-6,6-ethylene-4-en-3-one.
 3. The compound which is19-nor-20-spirox-6,6-ethylene-4,14-dien-3-one.
 4. A compound having theformula
 5. The compound of claim 4 which is6,6-ethylene-19-nor-20-spirox-4-en-3-OR, where R is hydrogen, loweralkylhaving one to six carbon atoms, loweralkanoyl having one to six carbonatoms, tetrahydropyranyl, or tetrahydrofuranyl.
 6. The compound which is6,6-ethylene-19-nor-20-spirox-4,14-dien-3-OR, where R is hydrogen, loweralkyl having one to six carbon atoms, loweralkanoyl having one to sixcarbon atoms, tetrahydropyranyl, or tetrahydrofuranyl.
 7. The compoundof claim 4 wherein R is hydrogen.
 8. The compound of claim 4 wherein Ris methyl.
 9. The compound of claim 4 wherein R is acetyl.
 10. Thecompound of claim 4 wherein R is tetrahydropyranyl.